Sesquiterpene lactones are the active constituents of a variety of medicinal plants used in traditional medicine. Parthenin the major sesquiterpenoid constituent of the weed, Parthenium hysterophorus L. (Compositae) exhibits significant medicinal and allelopathic activities.1 Medicinally, this compound has been found to be of interest for its anticancer, antibacterial, antiamoebic and antimalerial properties. Various modifications of parthenin have recently been carried out to obtain more potent analogues with lower toxicity and better activity. In recent years, the anti-cancer property of various sesquiterpenes has attracted a great deal of interest and extensive research work has been carried out to characterize the anti-cancer activity, the molecular mechanisms, and the potential chemo-preventive and chemo-therapeutic application of sesquiterpenoids. Cytotoxicity, as many other biological activities of sesquiterpene lactones, is known to be mediated by the presence of potentially alkylant structure elements capable of reacting covalently with biological nucleophiles, thereby inhibiting a variety of cellular functions2 which directs the cells into apoptosis.3-6 Sesquiterpene lactones (SLs) have been considered interesting leads to a new class of anticancer agents in the past. The anti-inflammatory activity of SLs has been corroborated using various assays and several studies reveal that they exert their activity by inhibiting the transcription factor NF-kB.7-10 Using helenalin and parthenolide as models, it is well established that DNA binding of NF-kB is prevented by alkylation of cysteine-38 in the p65/NF-kB subunit.7-11 There are strong indications that this is a general mechanism for SLs, which possess, α,β-unsaturated carbonyl structures such as α-methylene-β-lactones or, α,β-unsaturated cyclopentenones. These functional groups are known to react with nucleophiles, especially with the sulfhydryl group of cysteine, in a Michael-type addition (FIG. 1). Despite the plethora of experimental studies found in literature on the cytotoxicity of particular sesquiterpene lactones against many cell lines, little is known on the effects of different alkylant structure elements and of other structural factors on cytotoxicity in terms of SAR (structure-activity relationship). This, however, would be an important step in the direction of rational lead optimization.
In parthenin (1) we have two such active sites; one is the α-methylene-γ-butyrolactone and the other one is the cyclopentenone. Even though several groups worldover, have been working on the structural modification of parthenin, 12-16 either out of curiosity or with a view to develop secondary leads, to best of our knowledge, none of these reports reveal a focused and rational approach to the modification of parthenin in order to develop a SHAL (small molecule high affinity ligand) with better anticancer activity. Thus, there are literature reports which consider that the major activity of sesquiterpenoids has been attributed to the presence of α-methylene-γ-butyrolactone while few reports claim the importance of both cyclopentenone and α-methylene-γ-butyrolactone ring,17 whereas there has been neither any concrete SAR model proposed in literature for parthenin nor the mode of action of this molecule vis-à-vis the target protein. Even though, in literature, the importance of cyclopentenone ring as a potential alkylant structure in parthenin/SLs due to which the cytotoxicity has been attributed without any further rational effort to zero-in on the actual molecular target. The fact that 2-cyclopenten-1-one and its derivatives comprising the cyclopentenone nucleus has been established to be the inhibitors of the NF-kB factor, with anti-inflammatory, anti-proliferative, immune-suppressive, cytoprotective and antiviral activity,18 prompted us to propose the mechanism of action of parthenin involving such a pathway through design & synthesis of various parthenin analogues in such a way that we could unequivocally establish the SAR vis-à-vis the target of interaction. Thus, despite numerous biological activities of parthenin, no concrete SAR (Structure activity relationship) model for this molecule has been established till date. The present study deals with the design, synthesis and cytotoxic evaluation of parthenin through systematic and rational approach for structural modification in order to determine the SAR of the molecule unequivocally and the improved structures synthesized by us were found to be novel ligands with increased drug-likeness.